Biology Reference
In-Depth Information
The MMR pathway operates within the nucleosomal environment but the
impact of nucleosomal organization on MMR or vice versa is not understood.
Nucleosomes are highly stable protein-DNA complexes that sterically block
other DNA-binding proteins from accessing the chromatin. This could be a
hindrance to the diffusion of the MutS-MutL heterodimers. A recent study has
shown that the MMR complexes can cause disassembly or disruption of the
nucleosome.
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Acetylation of histone H3 lysine 56 within the nucleosomes both
reduces their affinity for DNA and enhances their disruption by the diffusing
MMR complexes. This disruption is passive as it requires only binding but not
hydrolysis of ATP. Therefore, the MMR complex carries out two functions: it
specifically recognizes mismatched DNA; and it creates a nucleosome-free
environment to allow other DNA repair proteins access when the MMR sliding
clamp performs passive DNA lesion-dependent chromatin remodeling.
While histone modifications have not been fully elucidated for the efficacy
or activities of MMR, recent studies do suggest that chromatin/histone modi-
fications are important in the MMR response to DNA damage.
As seen from this overview, there are multiple modifications that can occur
on all histones, including phosphorylations, acetylations, methylations, and
ubiquitylations. These modifications are common to all the DNA repair path-
ways. However, ribosylation appears to occur only for the DNA BER pathway.
For the base excision and the mismatch repair pathways, there are few studies
showing a link between histone modifications and the function of those
pathways, but recent studies suggest that there is some role for histone mod-
ifications and their activity, so more studies should be carried out.
Histone modifications appear to have many functions. They can mark the site
of damage and recruit specific DNA repair proteins to the damage. They can
also change the conformation of the histone such that it results in the opening
of the chromatin around the DSB to allow better access for the DNA repair
proteins. There can also be cross talk between some histone modifications to
regulate the repair process, from opening the chromatin to allow repair to
occur to closing the chromatin again once the DSB is fully repaired. There are
also modifications that occur that activate different repair pathways. The repair
pathway that becomes activated may therefore be a combination of the histone
modification and the type of damage that has happened—DSB versus an
interstrand cross-link versus a mismatched base. Further studies should be
able to determine which histone modifications are important and how cross talk
between them affects the function of these DNA repair pathways.
References
1. Evers B, Helleday T, Jonkers TJ. Targeting homologous recombination repair defects in cancer.
Trends Pharmacol Sci
2010;
:372-80.
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